In recent years, the therapeutic applications of cannabinoids from Cannabis sativa, a plant belonging to the Cannabaceae family, have significant interest. Cannabinoids, the principal compounds of this species, are predominantly classified into psychoactive and non-psychoactive types (Cristino et al., 2020; Mechoulam, 2019). The most studied cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are phytocannabinoids derived from the cannabis plant (Andre et al., 2016; Elmes et al., 2015). While THC is the psychoactive component of cannabis, CBD is non-psychoactive and has been widely studied for its potential therapeutic benefits (Scuderi et al., 2009). These compounds interact with the endocannabinoid system in humans, which plays a crucial role in regulating various physiological processes including pain sensation, immune response, and neuroprotection (Lowe et al., 2021). This system the commonly known G-protein-coupled receptor. Cannabinoid receptor (CBR1 and CBR2); and range of endogenous ligands and enzymes responsible for the synthesis and degradation of cannabinoids, emphasizing its complexity and significance in neuropharmacology (Keimpema et al., 2014; Lu and Mackie, 2021).

The endocannabinoid system is not limited to its two primary G-protein-coupled receptors, CBR1 and CBR2. It also includes a network of endogenous cannabinoids, such as anandamide and 2-arachidonoylglycerol, and enzymes like fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which synthesize and degrade these endocannabinoids. These components are crucial for the modulation of various physiological processes (Kilaru and Chapman, 2020). Importantly, cannabinoids interact with the endocannabinoid system to modulate neurotransmission and neuroinflammation, central mechanisms in the development and persistence of neuropathic pain (Guindon and Hohmann, 2009a; Woodhams et al., 2015). By binding to CBRs in the nervous system, these compounds can inhibit the release of neurotransmitters and pain signaling pathways, offering potential relief in conditions characterized by chronic pain and hyperalgesia (Finn et al., 2021; Mlost et al., 2019a). This interaction also suggests a broader role in neuroprotection and neuroplasticity, which could underlie their therapeutic benefits across a neuropathic disorders (Xu and Chen, 2015).

CBR1 is predominantly found in the brain and are involved in regulating neurotransmitter release (Busquets-Garcia et al., 2018), while CBR2 are mainly expressed in immune cells and peripheral tissues, where they modulate inflammatory processes (Turcotte et al., 2016). The endocannabinoid system presents a potential for therapeutic interventions targeting neurological disorders, where dysregulation of the endocannabinoid system has been implicated. The potential therapeutic applications of cannabinoids extend across a range of neurological conditions, including neurodegenerative diseases such as Alzheimer’s disease (Benito et al., 2007), Parkinson’s disease (Di Filippo et al., 2008), and Huntington’s disease (Pazos et al., 2008), and multiple sclerosis (MS) (Chiurchiu et al., 2018), epilepsy (Kwan Cheung et al., 2019), and chronic pain conditions like neuropathy (Maldonado et al., 2016). With the increasing prevalence of these conditions and the limited efficacy of existing treatments (Feigin et al., 2020), the exploration of cannabinoids as novel therapeutic agents has accelerated. Clinical trials have played a crucial role in evaluating the safety, efficacy, and mechanisms of action of cannabinoids in treating these neurological conditions.

Cannabinoids, particularly THC and CBD, have been explored for their ability to manage spasticity, neuropathic pain, and bladder dysfunction in MS patients (Baker et al., 2000; Fontelles and García, 2008; Zajicek and Apostu, 2011). Sativex, an oromucosal spray containing both THC and CBD, has been approved in several countries for the treatment of spasticity in MS (Giacoppo et al., 2017). Clinical trials have shown Sativex efficacy in reducing spasticity and improving quality of life in patients with refractory symptoms (Nurmikko et al., 2007; Vermersch, 2011). The underlying mechanisms of cannabinoids in MS appear to involve the modulation of immune cell activity, reduction of pro-inflammatory cytokine release, and preservation of neuronal integrity (Chiurchiu et al., 2018; Khan et al., 2022). In addition, another CBD-based oral product was approved by the United States Food and Drug Administration (USFDA) for the treatment of Dravet syndrome and Lennox-Gastaut syndrome (Wechsler et al., 2024; Laux et al., 2019), two rare and severe forms of childhood epilepsy (Sullivan et al., 2024). Cannabidiol success was supported by multiple randomized, placebo-controlled clinical trials that confirmed a significant reduction in seizure frequency in patients receiving CBD compared to those receiving placebo (Lattanzi et al., 2021; Miller et al., 2020; Patel et al., 2021). The exact mechanism by which cannabinoids reduce seizures is not fully understood, but it is believed to involve the modulation of voltage-gated ion channels, inhibition of glutamate release (Rosenberg et al., 2017), and increase the inhibitory GABAergic neurotransmission (Ruffolo et al., 2022). Therefore, restore the balance between excitatory and inhibitory signalling in the brain, which is often disrupted in epilepsy.

Chronic pain, particularly neuropathic pain, is one of the most challenging conditions to manage in the neurology field (Finnerup et al., 2021; Bernetti et al., 2021). Neuropathic pain is caused by damage to the nervous system and is often resistant to conventional analgesics, including opioids (Hange et al., 2022). The endocannabinoid system is thought to play a central role in modulating pain pathways (Greco et al., 2022), making cannabinoids a potential therapeutic option for patients with neuropathic pain. Clinical trials investigating cannabinoids in neuropathic pain have revealed contrary outcomes, with some studies reporting significant pain relief (Campos et al., 2021; Cumenal et al., 2021), while others showing less significant outcomes in regards to pain management (Selvarajah et al., 2010). However, cannabinoids are generally well-tolerated and offer a favourable safety profile compared to opioids (Pisani et al., 2021), making them an important alternative for patients seeking non-opioid pain management options.

Regardless of advancements in neurological therapeutics, significant limitations in the current treatment, particularly regarding efficacy and safety profiles. Many conventional therapies provide insufficient relief or pose substantial side effects, such as cognitive dulling, dependency, or even exacerbation of symptoms in long-term use. This highlights a clinical need for alternative therapeutic strategies, such as cannabinoids, which have shown in early trials to address these gaps effectively. This review examines the therapeutic potential of cannabinoids in managing cognition, pain, and spasticity in neurological conditions, with a strong focus on safety and tolerability. It aims to guide future research and clinical practice on how these compounds address specific symptoms and underpin safe usage.

This study analysed total of 47 completed clinical trials investigating the therapeutic potential of cannabinoids. While our study reviewed a broad range of clinical trials on cannabinoids, we specifically focused on those trials that primarily investigated CBD and THC. Although other cannabinoids such as Nabilone and Dronabinol were present in the dataset, our analysis cantered on understanding the effects and outcomes related to CBD and THC in treating neurological conditions. The 47 clinical trials revealed that the majority were in Phase 2, constituting a significant proportion of the dataset. The importance of Phase 2 trials is particularly relevant as these studies are designed to provide preliminary evidence on efficacy and a more precise assessment of safety, which are critical for subsequent larger-scale Phase 3 trials. This phase distribution underscores the developmental stage of cannabinoid use in neurological conditions and its potential readiness for more advanced clinical testing. Furthermore, the outcome measures across these trials primarily focused on efficacy in symptom management and safety profiles. For instance, pain management, spasticity reduction, and cognitive function improvements were commonly reported. The trials were selected based on their focus on cannabinoids and neurological disorders, and their characteristics are summarized in Table 1.

Our systematic review examined 47 clinical trials on cannabinoids in neurological conditions, with a focused analysis on the 13 trials involving CBD and THC, which represent about 27% of our sample. These trials are highlighted due to their significant insights into the therapeutic potential and regulatory considerations of CBD and THC. Including other cannabinoids provides a comparative context, enhancing our understanding of the unique effects of CBD and THC in neurological therapies. The results of this study highlight the growing body of evidence surrounding the therapeutic potential of cannabinoids, particularly CBD and THC, in treating a range of neurological disorders. The clinical trials reviewed in this analysis provide insights into how cannabinoids can be used to manage symptoms such as chronic pain, motor dysfunction, cognitive impairment, and behavioural disturbances. The diversity of conditions studied, from neurodegenerative diseases like Huntington’s and Alzheimer’s to more common disorders like migraine and neuropathic pain, underscores the wide-ranging potential of cannabinoids in neurology. However, while the therapeutic potential of these compounds is evident, the variability in trial design, outcome measures, and focus between CBD and THC requires careful consideration to understand the specific benefits and limitations of each cannabinoid.

One of the primary areas where cannabinoids have shown potential outcomes is in the management of chronic pain, which is a crucial mark of many neurological disorders. Both CBD and THC have been investigated for their analgesic properties, with most trials measuring pain severity and symptom relief as key outcomes. CBD trials, in particular, focused heavily on pain management in conditions such as TMJ disorder, migraine, and neuropathic pain, with outcomes often measured through patient-reported pain scores and functional limitations. The analgesic effects of CBD are presumed to be a result of its ability to modulate the endocannabinoid system and influence neurotransmitter release, particularly through the regulation of serotonin and dopamine pathways, which play critical roles in pain perception (Mlost et al., 2019b; Guindon and Hohmann, 2009b; Salaga et al., 2019). However, the exact mechanisms by which CBD produce its effects remain an active area of research, and the current trials provide only preliminary evidence for its use in chronic pain management. Additional studies with larger sample sizes and more rigorous designs are necessary to confirm these findings and to explore optimal dosing strategies for different types of pain.

In contrast, THC trials not only explored pain management but also extended into the treatment of motor and cognitive dysfunction, particularly in neurodegenerative diseases like Huntington’s and Alzheimer’s disease. THC’s effects on the endocannabinoid system involve its action as a partial agonist at CBR1 and CBR2 in the brain and peripheral nervous system. By activating these receptors, THC can influence motor control and reduce tremor severity, making it a potential candidate for treating conditions such as essential tremor and Parkinson’s disease (Buhmann et al., 2019). THC also has psychoactive effects, which can be both beneficial and limiting. In diseases like Alzheimer’s, THC has been shown to reduce agitation and behavioural disturbances, potentially providing relief for patients suffering from cognitive decline (Outen et al., 2021). However, its psychoactive properties raise concerns about side effects such as cognitive impairment and dizziness (Solimini et al., 2017), particularly in older adults who may already be vulnerable to cognitive issues (Beedham et al., 2020). This dual nature of THC providing both therapeutic benefits and psychoactive risks requires careful patient selection and close monitoring in clinical practice.

Another important aspect of this analysis is the difference in study phases between CBD and THC trials. The majority of the trials for both cannabinoids were concentrated in Phase 2, which is typically designed to assess efficacy and side effects in a larger cohort than Phase 1 trials. While Phase 2 studies provide valuable information on the potential benefits of cannabinoids, the lack of Phase 4 studies in the dataset is a significant limitation. Phase 4, or post-marketing surveillance, trials are essential for understanding the long-term effects and safety of cannabinoids when used in larger, more diverse populations outside the controlled environment of clinical trials (Resnik, 2007; Gough, 2005; Lunghi et al., 2022). The absence of Phase 4 data limits our ability to make definitive conclusions about the widespread use of CBD and THC in routine clinical practice. One of the key findings of this analysis is the comprehensive therapeutic scope of THC compared to CBD. While both cannabinoids are effective in managing pain, THC trials explored additional conditions such as dementia, behavioural disturbances, and motor disorders. The inclusion of conditions like Alzheimer’s disease in THC trials highlights its potential beyond pain relief, particularly in addressing the neuropsychiatric symptoms of neurodegenerative diseases (Cummings, 2021). This comprehensive range of applications for THC suggests that it may have a more useful role in neurology than CBD, although the psychoactive effects of THC remain a significant concern. However, CBD is often seen as a safer alternative due to its non-psychoactive nature, making it more suitable for patients who are sensitive to the mind-altering effects of THC (Benson, 2019; Stella, 2023). However, the narrow focus of CBD trials on pain and functional limitations may indicate that its therapeutic benefits are more restricted compared to THC, at least in the current body of evidence.

While THC’s psychoactive properties can limit its usability, strategies can be done to reduce these effects in clinical practice. Dose adjustments, based on patient response and tolerance, and the co-administration of CBD, which may counteract some of THC’s psychoactive effects, are viable approaches (Schecter and Cyr, 2022a; Kitdumrongthum and Trachootham, 2023). Furthermore, developing formulations that balance THC and CBD concentrations could influence the associated effect, potentially enhancing therapeutic outcomes while minimizing adverse effects (Schecter and Cyr, 2022b). Detailed guidelines for these strategies should be explored and defined through clinical research to ensure safe and effective use of cannabinoids in treating neurological conditions.

The safety profiles of both CBD and THC, as reported in these trials, suggest that both compounds are generally well-tolerated, with mild to moderate side effects being the most commonly reported issues. Dizziness, fatigue, and dry mouth were frequently observed, but these side effects did not appear to result in significant discontinuation rates or severe adverse events. This indicates that cannabinoids can be safely administered to patients with neurological disorders, provided that appropriate dosing and monitoring are in place. However, the limited number of trials and the absence of long-term safety data remain barriers to widespread clinical implementation. As the use of cannabinoids continues to grow, it will be critical to establish comprehensive safety guidelines and dosing protocols to ensure that the benefits of these therapies outweigh the risks for all patient populations.

As a limitation of our findings, future research should include multiple trial registries, such as the WHO’s International Clinical Trials Registry Platform (WHO ICTRP). Additionally, the variability in cannabinoid formulations and dosages across studies may affect the consistency and generalizability of results. Furthermore, many cannabinoid trials are short-term; long-term studies are needed to fully understand the safety and efficacy of cannabinoids for chronic neurological conditions. The potential biases identified through our risk-of-bias assessment may limit the reliability of our findings. Particularly, the high risk associated with unblinded studies and incomplete outcome reporting could have skewed the efficacy and safety profiles of cannabinoids reported in this review. The inclusion of studies with accurate methodological designs, including proper blinding and randomization, is also crucial to minimize bias. Lastly, potential publication biases and the varying legal and ethical landscapes surrounding cannabinoid use across countries must be considered, as these factors could significantly influence research outcomes and their interpretation. While our review confirms the therapeutic potential of cannabinoids for neurological conditions, the lack of standardized protocols and dosing regimens across the studies is a significant challenge. This variability can lead to inconsistent outcomes and complicates the determination of optimal therapeutic doses, potentially skewing the true effects of cannabinoids. These issues highlight the urgent need for future research to develop clear, evidence-based guidelines for cannabinoid treatment. Establishing standardized dosing protocols would not only improve the reliability of research findings but also facilitate their clinical application, enhancing patient safety and therapeutic outcomes.

The results of this analysis showed that both CBD and THC have significant potential as therapeutic agents for neurological disorders, particularly in managing pain, motor dysfunction, and behavioural disturbances. However, their different pharmacological profiles and side effect risks mean that each cannabinoid may be better suited to different patient populations and conditions. While THC’s broader range of applications in cognitive and motor symptoms positions it as a more multipurpose treatment option, the psychoactive risks associated with its use should not be ignored. On the other hand, CBD’s safety and non-psychoactive nature make it more preferred option for managing chronic pain, but its therapeutic benefits may be more limited. Future research should focus on addressing the gaps in long-term safety and efficacy data, as well as exploring the full potential of lesser-known cannabinoids and combination therapies to further enhance the treatment of neurological disorders.